Roxanna E. Rojas, MD, PhD

Gaining Insight into How TB Germ Hides From Immune System

While one-third of the world’s population is currently infected with TB, only about 10 percent of these people will develop TB disease in their lifetime. The remaining 90 percent have what is called latent or inactive TB, meaning their immune system can successfully fight the infection. The TB infection may remain inactive for a lifetime, although latent TB infection can become active if the person’s immune system becomes weakened (such as with HIV infection).

Roxana E. Rojas, MD, PhD, used an American Lung Association Biomedical Research Grant to investigate how the bacteria that causes TB, Mycobacterium tuberculosis, escapes recognition by the immune system and remains latent. Her goal was to gain information that could be used to design better vaccines.

M. tuberculosis appears to inactivate two types of key immune cells: macrophages and T lymphocytes. The TB bacteria primarily reside in macrophages, immune cells that engulf foreign material. Macrophages are activated by proteins called cytokines, which are secreted by T lymphocytes. Dr. Rojas studied the mechanisms that M. tuberculosis uses to inactivate T lymphocytes. She focused on molecules called glycolipids on the surface of the bacteria that affect T lymphocytes. Glycolipids prevent optimal interaction between T lymphocytes and macrophages, which is very important for the development of an effective immune response. In addition, mycobacterial glycolipids directly inactivate T cells, contributing to immune evasion.

Dr. Rojas made substantial progress toward her longterm goal of identifying and characterizing mycobacterial molecules that have a direct regulatory effect on T cell function. During the course of her research, she refined and expanded her original experiment to study the role of molecules other than the one she originally focused on. “This ALA-funded project and follow up studies stemming from it will have a direct impact in vaccine development,” she says. “These findings will help design improved anti- TB vaccines and therapeutic measures to limit TB damage in the lung.”

Since completing her research funded by the American Lung Association, Dr. Rojas received two grants from the National Institutes of Health.

Publications:
C.L. Lancioni, J.J. Thomas and R.E. Rojas Activation requirements and responses to TLR ligands in human CD4+ T cells: comparison of two T cell isolation techniques. J Immunol Methods. 2009 May 15;344(1):15-25.

S. Mahan, J. J. Thomas, W. H. Boom and R. E. Rojas. (2009). CD4(+) CD25(high) Foxp3(3+) regulatory T cells downregulate human Vdelta2(+) T-lymphocyte function triggered by anti-CD3 or phosphoantigen. Immunology. 127(3): 398-407.

Mahon R. N., Rojas R. E., Fulton S. A., Franko J., Harding C. V. and Boom W. H. (2009). Mycobacterium tuberculosis cell wall glycolipids directly inhibit CD4+ T-cell activation by interfering with proximal T-cell-receptor signaling. Infect. Immun., 77(10): 4574-83.

Drage, M.G., Tsai, H.-C., Pecora, N.D., Cheng, T.-Y., Arida, A.R., Shukla, S., Rojas, R.E., Moody, D.B., Boom, W.H., Sacchettini, J.C., and Harding, C.V. (2010). Mycobacterium tuberculosis lipoprotein LprG (Rv1411c) binds triacylated glycolipid agonists of Toll-like receptor 2. Nature Struct Mol Biol. 17: 1088-1095.

Christina L. Lancioni, Qing Li, Jeremy J. Thomas, Xuedong Ding, Bonnie Thiel, Michael G. Drage, Nicole D. Pecora, Assem G. Ziady, Samuel Shank, Clifford V. Harding, W. Henry Boom and Roxana E. Rojas. (2011). Mycobacterium tuberculosis lipoproteins directly regulate human memory CD4+ T cell activation via TLR2/1. Infection and Immunity. 79 (2): 663-673.

Robert N. Mahon, Obondo J Sande; Roxana E Rojas, Alan D Levine, Clifford V Harding, Henry Boom. 2012. Mycobacterium tuberculosis ManLAM inhibits T-cell-receptor signaling by interference with ZAP-70, Lck and LAT phosphorylation. Cell Immunol. 275(1-2): 98-105.

Qing Li, Xuedong Ding, Jeremy J. Thomas, Clifford V. Harding, Nicole D. Pecora, Assem G. Ziady, Samuel Shank, W. Henry Boom, Christina L. Lancioni and Roxana E. Rojas. 2012. Rv2468c, a novel Mycobacterium tuberculosis protein that co-stimulates human CD4+ T cells through VLA-5. J Leukoc Biol. 2012 Feb; 91(2): 311-2.